The long-term goal of this study is to identify mechanisms of viral inhibition of host defenses against infection. This information will enhance our understanding of the mechanisms of host defenses, and their contributions to health and disease. The poxvirus family includes some of the most virulent of all human pathogens. In part, the pathogenic effects of these viruses result from their abilities to counter host defenses against infection. Cowpox virus, a virus closely related to smallpox virus, encodes about two hundred proteins, many of which are involved in the viral inhibition of mammalian immune processes countering virus infection. In particular, this virus effectively inhibits inflammatory processes. Because of this property, it provides a unique system for the investigation of these processes. This system has already enabled us to identify five viral cytokine-response modifiers: an inhibitor of the interleukin-1-beta converting enzyme, a soluble interleukin-1 receptor, soluble secreted TNF receptors of two types, and a soluble protein similar to the ligand-binding portion of CD30. Our results suggest that cowpox virus encodes additional cytokine- response modifiers and inhibitors affecting non-specific host defenses, including inflammatory processes and apoptosis, and specific immune defenses. The specific aims of this study are to identify and characterize viral mechanisms contributing to viral inhibition of host defenses, with initial emphasis upon those mechanisms contributing to: 1) The modification of cytokine responses to infection. 2) The inhibition of apoptosis in virus-infected cells. 3) The inhibition of inflammatory responses. Knowledge of the mechanisms involved in the effective poxviral inhibition of host defenses against infection should assist the development of new therapies for a variety of conditions associated with infectious diseases, inflammatory diseases, autoimmune diseases, cancers, and organ transplantat n.